Tumor necrosis factor (TNF or TNFcz) is a key mediator in the establishment and maintenance of multiple inflammatory and autoimmue diseases, such as rheumatoid arthritis and inflammatory bowl disease. TNF- receptor signaling can simultaneously activate caspase 8, the transcription factor, NF-KB and the kinase, JNK. While activation of caspase 8 is required for TNF-induced apoptosis, and induction of NF-rd3 inhibits cell death, the precise function of JNK activation in TNF signaling is not clearly understood. We have shown that TNF-mediated caspase 8 cleavage and apoptosis require a sequential pathway involving JNK, Bid, and Smac/DIABLO. Activation of JNK induces caspase 8-independent cleavage of Bid at a distinct site to generate the Bid cleavage product jBid. Translocation ofjBid to mitochondria leads to preferential release of Smac/DIABLO, but not cytochrome c. The released Smac/DIABLO then disrupts the TRAF2-cIAP 1 complex. We propose that the JNK pathway is required to relieve the inhibition imposed by TRAF2-cIAP1 on caspase 8 activation and induction of apoptosis. In this proposal, we will explore the signaling mechanisms underlying the choice between cell survival and cell death in TNF response. Since TNF- mediated apoptosis plays a crucial role in both physiological and pathophysiological functions of TNF, understanding the regulation of TNF response will provide new avenues of therapeutic intervention for TNF- mediated inflammatory and autoimmue diseases.